Pharmaceutical composition for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists

ABSTRACT

The present invention relates to a pharmaceutical composition in the form of a storage-stable solution for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists, comprising a) an ultrashort-effective β-adrenoreceptor antagonist and/or a pharmaceutically acceptable salt thereof, b) water, and c) a cyclodextrin and/or a functional cyclodextrin derivative. The composition according to the invention has high stability, even without the presence of additional adjuvants.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/164,926, filed Oct. 19, 2018, which is a continuation ofU.S. patent application Ser. No. 15/248,845, filed Aug. 26, 2016, whichis a continuation of U.S. patent application Ser. No. 12/809,927, filedAug. 19, 2010, which is a national phase application under 35 U.S.C. §371 of International Application No. PCT/AT2008/000470, filed Dec. 22,2008, which claims priority to Austrian Patent Application No.A2107/2007, filed Dec. 21, 2007. The contents of the aforementionedapplication as are incorporated into the present application byreference.

BACKGROUND 1. Field of the Invention

The present invention relates to a pharmaceutical composition forparenteral administration of an ultrashort-effective βadrenoreceptorantagonist in the form of a solution.

2. Description of Related Art

Due to their very short elimination half-life, ultrashort-effectβ-adrenoreceptor antagonists such as esmolol hydrochloride, landiololhydrochloride (two cardioselective β₁ blockers) and flestololhydrochloride are used in the form of parenteral formulations,particularly in anaesthesia and in emergency and intensive caremedicine.

For the purpose of this invention, the term “ultrashort-effective” istaken to mean an active substance with an elimination half-life which isless than that of the β₁ blocker metoprolol (half-life t_(1/2)=90minutes). More particularly, the elimination half-life of theβ-adrenoreceptor antagonists used in accordance with the invention ispreferably less than 20 minutes.

One problem is the low stability of these active substances in aqueoussolution as they are hydrolytically split into free acids and alcohol(in the case of esmolol into pure acid and methanol) [e.g. Baaske D M,Dykstra S D, Wagenknecht D M, Karnatz N N Stability of esmololhydrochloride in intravenous solutions. Am J Hosp Pharm. 1994 Nov. 1; 51(21): 2693-6; Tamotsu Yasuda, Hiroyuki Kamiya, Yoko Tanaka, Go Watanbe,Ultrashort-acting cardioselective beta-blockade attenuates postischemiccardiac dysfunction in the isolated rat heart. Eur J Cardiothorac Surg2001; 19:647-652].

On the other hand the active substance concentration of, for exampleesmolol, used for administration is so high that these solutions areoften hypertonic. In addition, to stabilise these solutions alcohol inconcentrations of around 25% is added in many cases. Because of thesetechnical formulation problems, the use of esmolol in intensive caremedicine is associated with additional risks.

Commercially obtainable landiolol is, for example, currently onlyavailable in fixed formulations which have to be dissolved before beingused in intensive care medicine, leading to an unnecessary loss of time.Freeze-dried compositions containing landiolol are known from CN1827109A.

Attempts to solve the problems cited for esmolol include the addition ofdextrose [Wiest D B, Garner S S, Childress L M., Stability of esmololhydrochloride in 5% dextrose injection. Am J Health Syst Pharm 1995 Apr.1; 52 (7) 716-8.], adjusting the pH value to <6 [Rosenberg L S,Hostetler C K, Wagenknecht D M, Aunet D A., An accurate prediction ofthe pH changes due to degradation: correction for a “produced” secondarybuffering system. Pharm. Res. 1988 August; 5(8): 514-7.], as well as theaddition of propylene glycol in high concentrations[http://www.rxlist.com/cgi/generic3/esmolol.htm].

WO 85/04580 describes solutions of esmolol in a proportion by weight of0.1% to 30% which also include a buffer and ethanol in a proportion of 5to 60%.

In its claim 1, EP 0403578 claims an injectable, aqueous composition fortreating heart conditions, which has an effective quantity of esmolol(hydrochloride) in a proportion of 1 mg to 250 mg esmolol/ml solutionand 0.01 to 0.04 M buffer, and has a pH value in the range 4.5 to 5.5.

International publication WO 02/076446 describes an esmolol solutioncontaining 0.1 to 500 mg/ml esmolol hydrochloride, 0.01 to 2 M bufferand 1 to 500 mg/ml of an osmosis-adjusting agent.

European publication EP 1417962 describes pharmaceutical compositionsconsisting of 30 ml to 70 ml dilution with an proportion of 1500 mg to3500 mg esmolol or a pharmaceutically tolerable salt thereof.

SUMMARY

There are no known attempts to solve the cited problem for landiolol.

The aim of the present invention is to provide a composition forparenteral administration of ultrashort-effective β-adrenoreceptorantagonist, more particularly for injection or infusion, which on theone hand exhibits a high degree of storage stability and on the otherhand an osmolarity which is suitable for administration. The compositionshould exhibit vasoprotective properties, which is important especiallyat high active substance concentrations (e.g., in the case of esmolol).

Surprisingly it was found that the use of a cyclodextrin and/or afunctional cyclodextrin derivative to increase the stability of anultrashort-effective β-adrenoreceptor antagonist and/or apharmaceutically acceptable salt thereof in a suitable storage-stableaqueous solution for parenteral administration fulfils the aim of theinvention in an excellent manner.

In this aspect of the present invention the solution can also containother auxiliary substances, in particular buffers, preservation agents,organic solvents that can be mixed with water, salts, sugar alcoholsand/or sugar.

A further aspect of the present invention relates to a pharmaceuticalcomposition for parenteral administration of an ultrashort-effectiveβ-adrenoreceptor antagonist in the form of a storage-stable solution,essentially consisting of a) an ultrashort-effective β-adrenoreceptorantagonist and/or a pharmaceutically acceptable salt thereof b) waterand c) a cyclodextrin and/or a functional cyclodextrin derivative

DE 4207922 and US 2004/0053894 describe in general the use ofcyclodextrin in pharmaceutical compositions. The use of cyclodextrin inpharmaceutical compositions is also described in WO 2003/033025, US2003/021349 and in Ikeda et al., J. Pharm Sci. 2004, 93(7), 1659-1671.

It was found that by adding cyclodextrin and/or a functionalcyclodextrin derivative, the stability of ultrashort-effectiveβ-adrenoreceptor antagonists in pure aqueous solutions can be decisivelyincreased.

Surprisingly, ultrashort-effective β-adrenoreceptor antagonist solutionsconsisting solely of the ultrashort-effective β-adrenoceptor antagonist,cyclodextrin and water, are sufficiently storage-stable, even withoutthe presence of other auxiliary substances (such as buffer orosmolarity-adjusting agents known from the prior art) and, in terms ofosmolar properties are suitable for administration. This appliesparticularly in the pH range from 3 to 7.5, preferably from 5 to 7.

For the purpose of the present invention the term “storage-stable”denotes an aqueous solution, which in contrast to a solution producedthrough the dissolution of freeze-dried products, can be stored for alonger period of time without any significant breakdown of the containedactive substance taking place. Understood as “storage-stable” inparticular are aqueous solutions in which after one month less than 5%of the active substance has degraded.

As has been stated above, the pH value of the solution is preferably 3to 7.5, particularly preferably 5 to 7.

The concentration of the cyclodextrin or cyclodextrin derivative in thesolution is preferably 0.1% to 20% (w/v), preferably 0.25% to 7% (w/v),particularly preferably 0.5% to 4%.

The cyclodextrin or the functional cyclodextrin derivative is preferablyselected from the group comprising α-cyclodextrin, β-cyclodextrin,γ-cyclodextrin, functional derivatives and mixtures thereof.

“Functional cyclodextrin derivatives” is taken to mean allpharmaceutically acceptable derivatives of cyclodextrins in which theessential structure and size of the cyclodextrin molecules are retained.Considered as functional cyclodextrin derivatives in particular areesters with pharmaceutically acceptable acids and ethers, especiallylow-alkyl ethers. Particularly preferred cyclodextrin derivatives are(2-hydroxypropyl)-β-cyclodextrin and (sulfobutylether)-7β-cyclodextrin.

The ultrashort-effective β-adrenoreceptor antagonist used in thecomposition in accordance with the invention is preferably an activesubstance selected from the group comprising esmolol, landiolol andflestolol.

The concentration of the ultrashort-effective β-adrenoreceptorantagonist or the salt therefore in the solution can be 0.1% to 30%depending on the β-adrenoreceptor antagonist used. Preferredconcentrations in the case of esmolol or esmolol salts are 1 to 20%.Preferred concentrations in the case of landiolol or laniolol salts are1 to 20%. Preferred concentrations in the case of flestolol or flestololsalts are 0.1 to 10%.

The solution preferably has an osmolarity of 270 mosmol/l to 310mosmol/l, particularly preferably 280 mosmol/l to 300 mosmol/l. Thiscorresponds to an isotonic solution.

In the case of esmolol the composition in accordance with the inventionis preferably present in the form of a sales unit selected from thegroup comprising:

-   -   1 ml solution containing 10-20 mg esmolol or a salt thereof    -   2 ml solution containing 10-100 mg esmolol or a salt thereof    -   5 ml solution containing 50-500 mg esmolol or a salt thereof    -   10 ml solution containing 50-5000 mg, more particularly 2500 mg        esmolol or a salt thereof    -   50 ml solution containing 50-5000 mg esmolol or a salt thereof        100 ml solution containing 50-5000 mg esmolol or a salt thereof    -   250 ml solution containing 50-5000 mg esmolol or a salt thereof.

In the case of conventional products a 10 ml solution containing 100 mgesmolol as a “ready-to-use” product can be used directly for injection.Conventional compositions with high proportions of esmolol (moreparticularly 10 ml/2500 mg esmolol) must be diluted beforeadministration. In comparison, due to their vasoprotective properties,solutions in accordance with the invention can also be used with higherconcentrations of esmolol as “ready-to-use” products.

In the case of landiolol and/or festolol the composition according tothe invention is preferably available in the form of a sales unitselected from the group comprising

-   -   1 ml solution containing 5-20 mg landiolol or festolol or a salt        thereof    -   2 ml solution containing 5-100 mg landiolol or festolol or a        salt thereof    -   5 ml solution containing 10-500 mg landiolol or festolol or a        salt thereof    -   10 ml solution containing 10-5000 mg landiolol or festolol or a        salt thereof    -   25 ml solution containing 25-2500 mg landiolol or festolol or a        salt thereof    -   50 ml solution containing 50-5000 mg landiolol or festolol or a        salt thereof    -   100 ml solution containing 50-5000 mg landiolol or festolol or a        salt thereof    -   250 ml solution containing 50-5000 mg landiolol or festolol or a        salt thereof.

In conventional products containing landiolol, 50 mg of landiolol iscontained as dry substance. These products must first be made into asolution before injection.

In the compositions of landiolol according to the invention, thelandiolol is already present in solution in a stable form. In general,due to the vasoprotective properties of the compositions according tothe invention, comparatively higher concentrations of theultrashort-effective β-adrenoreceptor antagonists than in theformulations to date can be used.

The composition according to the invention can be produced in a knownmanner through mixing and subsequent dissolution of the constituents.

The composition according to the invention can be used in particular toproduce a medicinal product to reduce ventricular frequency in patientswith atrial fibrillation, atrial flutter and sinus tachycardia, inatrioventricular and AV node tachycardia, tachycardic supra- andventricular arrhythmias, in tachycardia and/or hypertension, before,during and after operations as well as in other emergency situations,for the prophylaxis and treatment of perioperative ischaemia, to treatunstable angina pectoris and acute myocardial infarction.

BRIEF DESCRIPTION OF DRAWINGS

The invention will be explained in more detail below with the aid ofexamples of embodiment and figures.

FIG. 1 shows the accelerated breakdown of a 5% esmolol referencesolution and compositions according to the invention at 75° C.

FIG. 2 shows the influence of freeze-drying on the accelerated breakdownof esmolol-cyclodextrin complexes in water at 75° C.

FIG. 3 shows the influence of the concentration of a-cyclodextrin on thestability of esmolol at 75° C.

FIG. 4 shows the influence of hydroxypropyl-β-cyclodextrin on thestability of esmolol at 75° C.

FIG. 5 shows the influence of α-cyclodextrin in increasingconcentrations on the stability of landiolol in aqueous solution at 70°C.

FIG. 6 shows the influence of 2-hydroxypropyl-β-cyclodextrin inincreasing concentrations on the stability of landiolol in aqueoussolution at 70° C.

FIG. 7 shows the influence of γ-cyclodextrin in increasingconcentrations on the stability of landiolol in aqueous solution at 70°C.

FIG. 8 shows the influence of the pH value on the stability of landiololin aqueous solution at 70° C.

FIG. 9 shows the influence of cyclodextrins (2%, w/v) in which landiololwas stored by means of concentrated suspensions on the stability ofaqueous landiolol solutions of 0.25% (w/v) at 70° C.

DETAILED DESCRIPTION Example 1 Production of(2-hydropropyl)-β-cylodextrin-esmolol Complexes

An equimolar quantity of (2-hyroxypropyl)-β-cyclodextrin was added to a5% esmolol solution and stirred for 6 hours.

Example 2 Production of α- and γ-cyclodextrin-esmolol Complexes

An equimolar quantity of α-cyclodextrin (Cavamax W6 Pharma, manufacturerWacker Chemie AG) (example 2a) or γ-cyclodextrin (Cavamax W8 Pharma,manufacturer Wacker Chemie AG) example 2b) was added to a 5% esmololsolution and stirred for 18 hours.

Example 3 Production of Cyclodextrin-Esmolol Complexes Example 3a

Esmolol and α-cyclodextrin are dissolved in final concentrations of 5%(w/v) (esmolol) and 14% (w/v) α-cyclodextrin) in water for injectionpurposes and stirred for 24 hours at room temperature.

Example 3b

Esmolol and optionally additionally α-cyclodextrin are dissolved in afinal concentration of 5% (w/v) (esmolol) or 14%, 7%, 4%, 2%, 1% and 0%(w/v) (α-cyclodextrin) in water for injection purposes and stirred for24 hours at room temperature.

Example 3c

Esmolol and optionally additionally hydroxypropol-β-cyclodextrin aredissolved in a final concentration of 5% (w/v) (esmolol) or 7% and 0%(w/v) (hydroxypropyl-β-cyclodextrin) in water for injection purposes andstirred for 24 hours at room temperature.

Example 4 Example of Comparison Production of a State-of-the-Art 5%Esmolol Solution for Injection

A parenteral solution was produced in accordance with the recipe set outin table 1.

TABLE 1 Composition of the parenteral esmolol solution SubstancesQuantity Esmolol HCl   500 mg Sodium acetate   34 mg Glacial acetic acid3.674 mg Propylene glycol   518 mg Ethanol   402 mg HCl or NaOH for pH3.5-5.5 q.s. Water ad 10 ml

Example 5 Investigations of the Stability of Parenteral EsmololSolutions

With solution described in examples 1 to 3, accelerated stability testswere carried out at a temperature of 75° C. After 0, 24, 45 and 70 hourssamples were taken which were diluted with distilled water (20 μlsample+180 μl water). The accelerated breakdown was determined by HPLCas follows:

For the qualitative and quantitative analyses a Hitachi Elite LaChromHPLC device with a diode array detector and a Waters Nova-Pak C18 4 μm3.9×150 mm column were used. The mobile phase consisted of (A) H₃PO₄ (10g/l) in water, adjusted to pH 2.35 with triethylamine (TEA) and (B)acetonitrile. The gradient used is set out in table 2.

TABLE 2 HPLC method Time (min) A (%) B (%)  0 82 18  7 82 18  8 60 40 1360 40 14 70 30 20 70 30 21 82 18 30 82 18

The flow rate was 1 ml/minute, the injection volume 20 μl. Esmololhydrochloride was detected at 274 nm. The retention time of esmololhydrochloride was on average 3.9 minutes, that of the principaldegradation product (“contaminant A” in table 3 below) was 1.7 minutes.To determine degradation the ratio of the principal degradation productto remaining esmolol hydrochloride was calculate and indicated inpercent (“degraded esmolol (%)”).

The results of these studies show a decisively increased stability ofthe solutions containing cyclodextrin.

FIG. 1 shows the accelerated degradation at 75° C. of the 5% esmololreference solution and esmolol cycoldextrin complexes in water [(⋄) 5%esmolol comparison solution with 0% cyclodextrin—example 3b; (X) 5%esmolol+γ-cyclodextrin—example 2b]; (▪) 5%esmolol+(2-hydroxypropyl)-β-cyclodextrin—example 1); (▴) 5%esmolol+α-cyclodextrin—example 2a]. The values are mean values of 3tests±SD.

FIG. 2 shows the influence of freeze drying on the accelerateddegradation of esmolol-cyclodextrin complexes in water at 75° C. [(⋄) 5%esmolol comparison solution with 0% cyclodextrin—example 3b; (X) 5%esmolol in 14% α-cyclodextrin solution without freeze drying—example 3a;(▪) 5% esmolol+α-cyclodextrin—example 2a with subsequent freeze dryingand reconstitution in water]. The values are mean values of 3 tests±SD.

FIG. 3 shows the influence of the concentration of α-cyclodextrin on thestability of an aqueous 5% esmolol solution at 75° C. [(▴) 5% esmololcomparison solution with 0% α-cyclodextrin—example 3b; (+) 5% esmolol+1%α-cyclodextrin—in accordance with example 3b; (○) 5% esmolol+2%α-cyclodextrin—in accordance with example 3b; (▪) 5% esmolol+4%α-cyclodextrin—in accordance with example 3b; (▴) 5% esmolol+7%α-cyclodextrin—in accordance with example 3b; (●) 5% esmolol+14%α-cyclodextrin—in accordance with example 3b;]. The values are meanvalues of 3 tests±SD.

FIG. 4 shows the influence of hydroxypopyl-β-cyclodextrin on thestability of an aqueous 5% esmolol solution at 75° C. [(▪) 5% esmololcomparison solution with 0% hydroxypropyl-β-cyclodextrin—example 3c; (○)5% esmolol+7% hydroxypropyl-β-cyclodextrin—in accordance with example3c]. The values are mean values of 3 tests±SD.

Example 6 Storage Stability of Esmolol Cyclodextrin Complexes

Table 3 shows the storage stability of esmolol cyclodextrin complexes(example 3a) compared with a state-of-the-art formulation (example 4) onthe basis of the increase in degradation products (=contaminants).

TABLE 3 Stability tests Stability tests 25° C./60% r.h. Storage time 0 60 6 months months months months Storage stability tests Esmololformulation Esmolol formulation without with Contaminants cyclodextrin(example 4) cyclodextrin (example 3a) CONTAMINANT 0 2.56 ± 0.53 0 1.94 ±1.06 A CONTAMINANT n.d. n.d. n.d. n.d. B CONTAMINANT n.d  n.d. n.d. n.d.C CONTAMINANT n.d. .018 ± 0.01 n.d. n.d. D Unknown 0 0.37 ± 0.04 0 0.38± 0.02 contaminants Total 0 3.11 0 2.24

Example 7 Determination of the Osmolarity

The osmolarity/reduction in freezing point vis-a-vis water wasdetermined with a Knauer semi-micro-osmometer. In order to be able todetermine the osmolarity with this osmometer the samples are cooled tofreezing in the osmometer.

The 5% solution with α-cyclodextrin in accordance with example 3a has anosmolarity of 290 mosmol/l. This corresponds to an isotonic solution asthe range of isotonia extends from 281 to 297 mosmol/l. Solutionsof >310 mosmol/l would be described as hypertonic and solutions of <270mosmol/l classified as hypotonic.

Example 8 Production and Stability Testing of Cyclodextrin-LandiololComplexes

Landiolol was dissolved in purified water at a concentration of 0.25%(m/v). Subsequently α-cyclodextrin (Cyclolab, Budapest),2-hydroxypropyl-β-cyclodextrin (CTD, Inc., Florida) and γ-cyclodextrin(ISP, Germany) was added in final concentrations of 0%, 0.5%, 1%, 2% and7% (w/v). The solutions were heated to 70° C. and the stability oflandiolol determined in accordance with the HPLC method described inexample 5. Landiolol was detected at 220 nm. The retention time oflandiolol hydrochloride was on average 10.5 minutes, that of theprincipal degradation product 1.4 minutes. To determine the degradationthe ratio of the principal degradation product to the remaininglandiolol hydrochloride was calculated and indicated in percent(“degraded landiolol (%)”). The results of this study are shown in FIG.5-7 . The shown values are mean values of 3 tests±SD. FIG. 5 shows theinfluence of 0% (▪), 0.5% (X), 1% (○), 2% (Δ), 4% (▴) and 7% (▭)α-cyclodextrin on the stability of landiolol at 70° C.

FIG. 6 shows the influence of 0% (▪), 0.5% (X), 1% (○), 2% (Δ), 4% (▴)and 7% (▭) hydroxypropyl-β-cyclodextrin on the stability of landiolol at70° C.

FIG. 7 shows the influence of 0% (♦), 0.5% (▭), 1% (X), 2% (Δ), 4% (▪)and 7% (○) γ-cyclodextrin on the stability of landiolol at 70° C.

Example 9 Evaluation of the Influence of the pH Value on the Stabilityof Landiolol

Landiolol was dissolved in purified water at a concentration of 0.25(w/v). The pH value was then adjusted to 3; 4; 5; 5.5; 6; 6.5; 7 and 8.The solutions were heated to 70° C. and the stability of landiololdetermined with the HPLC method described in examples 5 and 8. Theresults of these studies are shown in FIG. 8 . These show thedegradation of landiolol at pH 3.0 (⋄), pH 4.0 (X), pH 5.0 (▭), pH 5.5(Δ), ph 6.0 (▴), pH 6.5 (♦), pH 7.0 (○) and pH 8.0 (▪). The shown valuesare mean values of 3 tests±SD.

Example 10 Stability Tests of Cyclodextrin-Landiolol Complexes Producedby Means of Concentrated Suspensions

Landiolol and α-cyclodextrin (Cyclolab, Budapest),2-hydroxypropyl-β-cyclodextrin (CTD Inc., Florida) or γ-cyclodextrin(ISP, Germany) were suspended in purified water in a concentration of10% landiolol (w/v) and 80% cyclodextrin (w/v) and stirred for two hoursat room temperature. After 5 minutes of ultrasound treatment thesuspensions were diluted in stages so that the final concentration oflandiolol was 0.25% (w/v). These solutions were incubated at 70° C. andthe taken sample were analysed by means of the HPLC method described inexamples 5 and 8. The results of this study are set out in FIG. 9 .These show the influence of 2% α-cyclodextrin (▴), 2%2-hydroxypropyl-β-cyclodextrin (Δ) and 2% γ-cyclodextrin (○) on thestability of landiolol at 70° C. The shown values are mean values of 3tests±SD.

Example 11 Vasoprotective Effect of Cyclodextrin on IntravenouslyAdministered Ultrashort-Effect β-Adrenoceptor Antagonists

Solutions of said β-adrenoreceptor antagonists with or withoutcyclodextrin were chronically infused into rats via the jugular vein fora longer period. It can be seen that said beta-adreno-receptorantagonists in solutions containing cyclodextrin bring aboutconsiderably less endothelial and vascular damage than the use of aconventional solution.

What is claimed is:
 1. A pharmaceutical composition comprising: a)landiolol or a pharmaceutically acceptable salt thereof at aconcentration from 0.005 to 2% (w/v); b) water; and c)2-hydroxypropyl-β-cyclodextrin at a concentration from 0.1 to 20% (w/v).2. The pharmaceutical composition of claim 1, wherein the pH value ofthe composition is 3 to 7.5.
 3. The pharmaceutical composition of claim2, wherein the pH value of the composition is 5 to
 7. 4. Thepharmaceutical composition of claim 1, wherein the concentration of2-hydroxypropyl-β-cyclodextrin is 0.1% to 15% (w/v).
 5. Thepharmaceutical composition of claim 4, wherein, the concentration of2-hydroxypropyl-β-cyclodextrin is 0.25% to 7% (w/v).
 6. Thepharmaceutical composition of claim 5, wherein the concentration of2-hydroxypropyl-β-cyclodextrin is 0.5% to 4%.
 7. The pharmaceuticalcomposition of claim 1, wherein the concentration of the landiolol orpharmaceutically acceptable salt thereof is 0.01% to 1.0% (w/v).
 8. Thepharmaceutical composition of claim 1, wherein the composition has anosmolarity of 270 mosmol/l to 310 mosmol/l.
 9. The pharmaceuticalcomposition of claim 8, wherein the composition has an osmolarity of 280mosmol/l to 300 mosmol/l.
 10. The pharmaceutical composition of claim 1,wherein the composition is present in the form of a sales unit selectedfrom the group consisting of: 1 ml solution containing 5-20 mg landiololor a salt thereof, 2 ml solution containing 5-40 mg landiolol or a saltthereof.
 11. A method of reducing heart beat frequency in a patientcomprising administering a composition of claim 1 to a patient, wherebythe heart beat frequency in the patient is reduced.
 12. The method ofclaim 11, wherein the patient has atrial fibrillation, atrial flutter,sinus tachycardia, atrioventricular tachycardia, AV node tachycardia,supraventricular tachycardia, ventricular arrhythmias, perioperativeischaemia, unstable angina pectoris, or acute myocardial infarction.